This invention relates to prostate cancer, and more particularly to methods and compositions for inhibiting the proliferation of prostate cancer cells.
The prostate gland is located between the bladder and the rectum and wraps around the urethra. The prostate is composed of glandular tissue that produces a milky fluid and smooth muscles that contract during sex and squeeze this fluid into the urethra where it mixes with other fluid and sperm to form semen. The prostate gland converts testosterone to a more powerful male hormone, dihydrotestosterone, which affects the size of the gland and plays an important role in prostate cancer.
Prostate cancer is a malignant tumor that arises in the prostate gland and can eventually spread through the blood and lymph fluid to other organs, bones, and tissues. Prostate cancer is the most commonly diagnosed cancer in the U.S., and it is the second leading cause of cancer death in American men after non-melanoma skin cancer. Although prostate cancer is just as common in Japan as in the United States, death rates from prostate cancer are significantly lower in Japan. It is unlikely that these differences are all genetic, because Japanese men who migrate to the United States die of prostate cancer with increasing frequency as a function of the number of years they reside in the United States. It is possible that this paradox could be explained, at least in part, by dietary factors.
Benign prostatic hyperplasia (BPH) is a benign enlargement of the prostate gland caused by the growth of both glandular and stromal tissues. Because the prostate enlargement in BPH is affected by testosterone, many men are concerned that it may be related to prostate cancer. A ten-year study, however, found no higher risk for prostate cancer in men with or that have experienced BPH. BPH develops in the inner zone of the prostate (i.e., predominantly stromal cells), while cancer tends to develop in the outer area (i.e., epidermal cells).
It is reported herein that the expression of the androgen receptor was inhibited by quercetin. Accordingly, the invention provides for methods of monitoring the proliferation of cultured prostate cancer cells in the presence of quercetin, methods of treating an individual with prostate cancer or at risk of developing prostate cancer, and methods of reducing the risk of recurrence of prostate cancer in an individual who had previously been treated for prostate cancer. Methods of the invention further include treating an individual with benign prostatic hyperplasia (BPH) as well as methods of screening for compounds that inhibit the proliferation of prostate cancer cells. The invention provides for compositions and articles of manufacture containing quercetin in particular formulations, or quercetin with a second compound that also exerts an effect on the androgen receptor.
In one aspect, the invention provides methods of monitoring the proliferation of cultured prostate cancer cells in the presence of quercetin. Such a method includes contacting cultured prostate cancer cells with quercetin, and determining the level of expression of a gene encoding an androgen receptor. Generally, a decrease in androgen receptor expression in the prostate cancer cells indicates an inhibitory effect by quercetin on the proliferation of the prostate cancer cells. Representative prostate cancer cell lines include LNCaP cells or LAPC-4 cells.
In another aspect, the invention provides methods of treating an individual with prostate cancer or at risk of developing prostate cancer. Methods of treating an individual with prostate cancer or at risk of developing prostate cancer include identifying an individual with prostate cancer or at risk of developing prostate cancer, and administering a dose of quercetin to the individual that is effective to inhibit expression of a gene encoding an androgen receptor. The method also can include monitoring expression of the gene encoding the androgen receptor in the individual. Decreasing androgen receptor expression inhibits the proliferation of prostate cancer cells, thereby treating the individual. For example, quercetin can be administered to a human, and in an amount of from about 50 mg/kg to about 1000 mg/kg. Quercetin can be administered orally, transdermally, intravenously, intraperitoneally, or using an implant.
In still another aspect, the invention provides for methods of reducing the risk of recurrence of prostate cancer in an individual who previously had been treated for prostate cancer. Such a method includes the step of administering a dose of quercetin to the individual that is effective to inhibit expression of a gene encoding an androgen receptor. The method can further include the step of monitoring expression of the gene encoding the androgen receptor in the individual. Generally, decreasing androgen receptor expression inhibits the proliferation of prostate cancer cells, thereby reducing the risk of recurrence of prostate cancer in the individual. The individual may have previously undergone a radical prostectomy.
In yet another aspect, the invention provides methods of treating an individual with benign prostatic hyperplasia (BPH). This method includes identifying an individual with BPH, and administering a dose of quercetin to the individual that is effective to inhibit expression of a gene encoding an androgen receptor. The method also can include monitoring expression of the gene encoding the androgen receptor in the individual. Inhibiting the expression of a gene encoding an androgen receptor thereby treating the BPH in the individual.
The invention additionally provides methods of screening for compounds that inhibit the proliferation of prostate cancer cells, including contacting prostate cancer cells with a compound, and determining the transactivating ability of an androgen receptor. The method also can include monitoring the transactivating ability of the androgen receptor in the prostate cancer cells. Decreased transactivating ability of the androgen receptor in the prostate cancer cells compared to prostate cancer cells not contacted with the compound indicates a compound that inhibits the proliferation of prostate cancer cells.
The invention additionally provides methods of screening for compounds that inhibit the proliferation of prostate cancer cells, including contacting prostate cancer cells with a compound, and determining the level of expression of a gene encoding an androgen receptor. The method also can include monitoring expression of the gene encoding the androgen receptor in the prostate cancer cells. Decreased androgen receptor expression in the prostate cancer cells compared to prostate cancer cells not contacted with the compound indicates a compound that inhibits the proliferation of prostate cancer cells. Prostate cancer cells such as LNCaP cells or LAPC-4 cells can be used in this method.
Further, the invention provides compositions that include quercetin, one or more compounds that have a particular mechanism of action (i.e., inhibiting expression of a gene encoding an androgen receptor, inhibiting nuclear localization of an androgen receptor, and inhibiting the transactivating ability of an androgen receptor) and a pharmaceutically acceptable carrier. Representative examples of compounds having particular mechanisms of action include silymarin, silibin, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), perillyl alcohol (POH) or a derivative thereof, resveratrol, flufenamic acid, tea polyphenols, and anti-androgen compounds. It is a feature of the invention to provide such a composition in the form of an article of manufacture (e.g., a kit). Such an article of manufacture can include packaging material comprises instructions for using the composition to inhibit the expression of a gene encoding an androgen receptor in an individual.
In another aspect of the invention, there are provided compositions that include quercetin and that are formulated for transdermal delivery to the prostate of an individual. Delivery to the prostate typically inhibits expression of a gene encoding an androgen receptor. In addition, the invention provides compositions that include quercetin and that are formulated for implantation near the prostate of an individual. Generally, implantation near the prostate inhibits expression of a gene encoding an androgen receptor.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the drawings and detailed description, and from the claims.